Multi-Responsive Drug Release Of Hydroxyapatite/Natural Polymer-Based Hybrid Micro/Nanocarriers

In recent years,due to the poor control performance and therapeutic effect of single responsive drug carriers,multi-responsive drug carriers are favored by many researchers.Ti₃C₂ MXene,an emerging two-dimensional material,has potential applications in remotely controllable drug release field because of its unique ultra-thin two-dimensional plane structure,high photothermal conversion efficiency and easy to modify.Hydroxyapatite（HAP）has been widely used in the design of drug carriers due to its excellent biocompatibility,large specific surface area,outstanding mechanical properties and excellent p H response.In this study,HAP,chitosan（CS）,hyaluronic acid（HA）,Ti₃C₂ and gold nanorods（Au NRs）with synergistically enhanced near infrared（NIR）responsiveness,were employed to prepare p H/NIR multi-responsive hollow microcapsules and nano-hybrid carriers with excellent drug loading efficiency and biocompatibility.This paper provides a new idea for the design of intelligent remotely controllable drug carriers.This thesis was divided into the following two parts.Firstly,the pH/NIR multi-responsive HAP/CS/HA/MXene/Au NRs microcapsules were prepared by layer-by-layer self-assembly technique using hollow HAP,CS/HA multilayers,Ti₃C₂ MXene nanosheets and Au NRs.Doxorubicin hydrochloride（DOX）was used as the model drug to investigate the drug loading and smart release properties of the hybrid microcapsules.The hybrid microcapsule has excellent drug loading capacity（drug encapsulation rate was around 83.9%）because of the hollow structure and large specific surface area of HAP.CS/HA multilayers deposited on the surface of hollow HAP could delay the burst release of DOX at the initial stage of drug release.Finally,MXene and Au NRs with NIR response were installed on the surface of hybrid microcapsules to improve the photothermal conversion efficiency of microcapsules.In addition,due to the dissolution of HAP under acidic conditions,as well as the synergistic enhancement of photothermal effect between Ti₃C₂ and Au NRs,microcapsules exhibited excellent p H/NIR dual-responsive drug release properties.The drug release of microcapsules reached 76.26%at p H 4.5 upon NIR laser irradiation.Cytotoxicity test showed that microcapsules had very low cytotoxicity and excellent biocompatibility.Next,the nHAP/CS/Ti₃C₂@Au NRs nano-hybrid carrier was prepared by coating CS and in-situ growing NIR responsive Ti₃C₂@Au NRs nanosheets on the surface of nano-hydroxyapatite particles（n HAP）.n HAP/CS/Ti₃C₂@Au NRs nanohybrid carriers exhibited excellent p H responsiveness due to their small size,which enabled n HAP and CS to be fully dissolved in acidic media.Meanwhile,Au NRs grown in situ on the surface of Ti₃C₂ could effectively protect Ti₃C₂,which effectively delayed its oxidation and prevented the aggregation of Ti₃C₂ nanosheets.In addition,due to the synergistic photothermal response between Ti₃C₂ and Au NRs,Ti₃C₂@Au NRs nanosheets exhibited outstanding photothermal conversion efficiency.Photothermal experiments showed that,compared with the n HAP/CS/Ti₃C₂ nano-carrier,n HAP/CS/Ti₃C₂@Au NRs nano-hybrid carrier had better photothermal conversion ability,photothermal stability and structural stability.Furthermore,SH-PEG-CH₃ was used to modify Au NRs to replace and remove CTAB,which could effectively improve the biocompatibility of the nanohybrid carrier.Due to the disintegration of n HAP and CS in acidic medium,as well as the synergistic enhancement of photothermal properties from Ti₃C₂@Au NRs nanosheets,the nanohybrid carrier showed excellent p H/NIR dual response drug release performance and extremely low cytotoxicity in drug delivery experiments,which had a broad application prospect in the field of multifunctional drug delivery.